Transcription factor 21 accelerates vascular calcification in mice by activating the IL-6/STAT3 signaling pathway and the interplay between VSMCs and ECs.

Vascular calcification is caused by the deposition of calcium salts in the intimal or tunica media layer of the aorta, which increases the risk of cardiovascular events and all-cause mortality. However, the mechanisms underlying vascular calcification are not fully clarified. Recently it has been shown that transcription factor 21 (TCF21) is highly expressed in human and mouse atherosclerotic plaques. In this study we investigated the role of TCF21 in vascular calcification and the underlying mechanisms. In carotid artery atherosclerotic plaques collected from 6 patients, we found that TCF21 expression was upregulated in calcific areas. We further demonstrated TCF21 expression was increased in an in vitro vascular smooth muscle cell (VSMC) osteogenesis model. TCF21 overexpression promoted osteogenic differentiation of VSMC, whereas TCF21 knockdown in VSMC attenuated the calcification. Similar results were observed in ex vivo mouse thoracic aorta rings. Previous reports showed that TCF21 bound to myocardin (MYOCD) to inhibit the transcriptional activity of serum response factor (SRF)-MYOCD complex. We found that SRF overexpression significantly attenuated TCF21-induced VSMC and aortic ring calcification. Overexpression of SRF, but not MYOCD, reversed TCF21-inhibited expression of contractile genes SMA and SM22. More importantly, under high inorganic phosphate (3 mM) condition, SRF overexpression reduced TCF21-induced expression of calcification-related genes (BMP2 and RUNX2) as well as vascular calcification. Moreover, TCF21 overexpression enhanced IL-6 expression and downstream STAT3 activation to facilitate vascular calcification. Both LPS and STAT3 could induce TCF21 expression, suggesting that the inflammation and TCF21 might form a positive feedback loop to amplify the activation of IL-6/STAT3 signaling pathway. On the other hand, TCF21 induced production of inflammatory cytokines IL-1ß and IL-6 in endothelial cells (ECs) to promote VSMC osteogenesis. In EC-specific TCF21 knockout (TCF21ECKO) mice, VD3 and nicotine-induced vascular calcification was significantly reduced. Our results suggest that TCF21 aggravates vascular calcification by activating IL-6/STAT3 signaling and interplay between VSMC and EC, which provides new insights into the pathogenesis of vascular calcification. TCF21 enhances vascular calcification by activating the IL-6-STAT3 signaling pathway. TCF21 inhibition may be a new potential therapeutic strategy for the prevention and treatment of vascular calcification.

Association of stent-induced changes in coronary geometry with late stent failure: Insights from three-dimensional quantitative coronary angiographic analysis.

BACKGROUND: The relationship between vessel angulation and large changes in vessel geometry after stent implantation and the occurrence of stent failure still remains unclear. We sought to investigate the association of the change in the coronary bending angle after stenting and the risk for late stent failure by three-dimensional quantitative coronary angiography (3D QCA). METHODS: The bending angle in coronary lesions that presented with late stent failure and those without stent failure was computed during the cardiac cycle, before and after stenting using a recently developed 3D QCA software. RESULTS: A total of 40 lesions with stent failure (cases) were successfully matched to 47 lesions without stent failure (controls).The mean duration to follow-up coronary angiography was 1,011 days in cases and 1,109 days in the control group (P = 0.14). In stent failure, the systolic bending angle after stenting was smaller (14.45° [12.18, 17.68] versus 18.20° [14.00, 20.30], P = 0.01), while the stent-induced change in systolic bending angle was significantly larger (4.15° [1.13, 7.20] versus 1.80° [-1.90, 4.40], P = 0.004). Multivariable logistic regression analysis suggested that systolic bending angle after stenting (odds ratio: 0.88; 95% CI: 0.79-0.99; P = 0.03), and decrease in systolic bending angle after stenting (odds ratio: 1.13; 95% CI: 1.02-1.26; P = 0.03) were predictors of stent failure. CONCLUSIONS: Our study suggests that a change in the natural tortuous course of the coronaries by stent implantation with the decrease in coronary bending angle is a potentially major contributor in stent failure.

Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy.

BACKGROUND: Our previous studies demonstrated that luteolin, which is rich in flavones, has various biological properties and can exert anti-oxidant, anti-inflammatory and anti-apoptotic activities. However, its effect on ox-LDL-induced macrophage lipid accumulation and apoptosis has not been revealed. AIMS: This study aimed to explore the role of luteolin in ox-LDL-induced macrophage-derived foam cell formation and apoptosis and to delineate the underlying mechanism. METHODS: Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (50 µg/ml) for 24 h and then pretreated with 25 µM luteolin for another 24 h. The effects of luteolin on lipid accumulation in RAW264.7 cells induced by ox-LDL were assayed using Oil red O staining and high performance liquid chromatography (HPLC). Apoptosis was confirmed by acridine orange/ethidium bromide (AO/EB) staining, flow cytometric analysis and the TUNEL assay. Immunofluorescence, Western blot and monodansylcadaverine (MDC) staining analyses were then used to further investigate the molecular mechanisms by which luteolin protects macrophages from ox-LDL-induced foam cell formation and apoptosis. 3-Methyladenine (3-MA), an autophagy inhibitor, was used as a positive control. RESULTS: Treatment with 25 µM luteolin not only significantly attenuated ox-LDL-induced macrophage lipid accumulation but also decreased the apoptotic rate of RAW264.7 cells, the number of TUNEL-positive macrophages and the expression of Bax, Bak, cleaved caspase-9 and cleaved caspase-3. In addition, luteolin pretreatment significantly increased autophagosome formation and Beclin-1 activity, thus increasing the ratio of LC3-II/LC3-I. Moreover, these effects were abolished by 3-MA. CONCLUSIONS: Taken together, these results highlight that luteolin treatment attenuates foam cell formation and macrophage apoptosis by promoting autophagy and provide new insights into the molecular mechanism of luteolin and its therapeutic potential in the treatment of atherosclerosis.

Coronary Plaque Characteristics Affect No-Reflow During Primary Percutaneous Coronary Intervention: A Pooled Analysis of 14 Observational Studies Using Intravascular Ultrasound.

The association between coronary plaque composition and no-reflow during percutaneous coronary intervention (PCI) is still debated. We performed a systematic literature search using MEDLINE, Embase, Cochrane, and Ovid databases for intravascular ultrasound (IVUS) studies evaluating the relationship between coronary plaque characteristics and no-reflow after PCI. Fourteen observational trials were included in the meta-analysis, including 1457 patients (237 in the no-reflow group, 1220 in the normal reflow group). Pooled analysis indicated that the no-reflow group had a significantly higher absolute volume of fibrofatty plaque (weighted mean differences [WMD], 4.94 mm(3); 95% confidence interval [CI], 1.83-l8.06; P = .002), external elastic membrane cross-sectional area (EEM-CSA) (WMD, 3.40 mm2; 95% CI, 2.22-4.58; P = .00001), plaque area (WMD, 4.06 mm(2); 95% CI, 2.24-5.89; P = .0001), and artery remodeling index (WMD, 0.09; 95% CI, 0.06-0.13; P = .00001), and a smaller percentage of fibrous plaque (WMD, -5.89 %; 95% CI, -0.66 to -11.12; P = .03) than in the normal reflow group. There were no significant differences in the other plaque components between the two groups. This meta-analysis confirmed that high absolute volume of fibrofatty plaque, EEM-CSA, plaque area, and coronary artery remodeling index, and a decreased percentage of fibrous plaque as detected by IVUS in culprit lesions, are linked with the development of the no-reflow phenomenon after PCI.

[Peroxisome proliferator-activated receptor α/γ agonist tesaglitazar stabilizes atherosclerotic plaque in diabetic low density lipoprotein receptor knockout mice].

OBJECTIVE: To investigate the effects of peroxisome proliferator-activated receptor (PPAR) α/γ agonist on atherosclerotic plaque stabilization in diabetic LDL receptor knockout (LDLr-/-) mice. METHODS: Female 4-week-old LDLr-/- mice fed with high-glucose and high-fat diet for 4 weeks were randomly divided into three groups (n = 15 each): control group (only fed with high-glucose and high-fat diet), diabetic group [induced by high-glucose and high-fat diet combined with a low-dose of streptozotocin (STZ)] without tesaglitazar and with tesaglitazar (20 µg/kg oral treatment). After 6 weeks, the mice were sacrificed, body weight, fasting blood glucose (Glu), total cholesterol (TC), triglyceride (TG) levels were measured. The expression of ICAM-1, VCAM-1, MCP-1 in the brachiocephalic atherosclerotic lesions were determined by Western blot and immunohistochemistry, respectively. Brachiocephalic artery was prepared for morphologic study (HE, oil red O, Sirius red staining) and immunohistochemical analysis (macrophage surface molecule-3, α-smooth muscle actin), respectively. RESULTS: Serum TC [(32.34 ± 3.26) mmol/L vs. (16.17 ± 1.91) mmol/L], TG [(3.57 ± 0.99) mmol/L vs. (2.21 ± 0.11) mmol/L] and Glu [(15.21 ± 4.67) mmol/L vs. (6.89 ± 0.83) mmol/L] levels were significantly higher in diabetic group than in the control group (all P < 0.01). The expression of ICAM-1 (2.31 ± 0.35 vs.1.34 ± 0.21), VCAM-1 (1.65 ± 0.14 vs.0.82 ± 0.26), MCP-1 (2.27 ± 0.16 vs.1.56 ± 0.23) were significantly upregulated in diabetic group compared with control group (all P < 0.01). Brachiocephalic atherosclerotic plaque area [(4.597 ± 1.260)×10(3) µm(2) vs. (0.075 ± 0.030)×10(3) µm(2)], lipid deposition [(47.23 ± 2.64)% vs. (9.67 ± 1.75)%], Mac-3 positive area [(19.15 ± 3.51)% vs. (1.72 ± 0.16)%], α-smooth muscle actin [(5.54 ± 1.17)% vs. (2.13 ± 0.41)%] and collagen content [(4.27 ± 0.74)% vs. (0.43 ± 0.09)%] were all significantly larger/higher in diabetic LDLr-/- mice than in the control group (all P < 0.01). While tesaglitazar treatment significantly reduced serum TC [(30.47 ± 3.18) mmol/L], TG [(3.14 ± 0.71) mmol/L] and Glu [(7.92 ± 1.28) mmol/L] levels (all P < 0.01). Similarly, the expression of ICAM-1 [(1.84 ± 0.22)], VCAM-1 [(1.27 ± 0.11)], MCP-1 [(1.83 ± 0.24)], brachiocephalic atherosclerotic lesion area[(1.283 ± 0.410)×10(3) µm(2)], lipid deposition[(23.52 ± 1.39)%] were also significantly reduced by tesaglitazar (all P < 0.05). Moreover, tesaglitazar increased α-smooth muscle actin [(9.46 ± 1.47)%] and collagen content [(6.32 ± 1.15)%] in diabetic LDLr-/- mice (all P < 0.05). In addition, lipid deposition and Mac-3 positive areas [(10.67 ± 0.88)% vs. (15.83 ± 1.01)%] in the aortic root were also reduced in tesaglitazar treated diabetic LDLr-/- mice (P < 0.01). CONCLUSIONS: Tesaglitazar has anti-inflammatory effects in the diabetic LDLr-/- mice. Tesaglitazar could reduce lipid deposition, increase collagen and α-SMA content in the brachiocephalic atherosclerotic lesions, thus, stabilize atherosclerotic plaque in this model.

A meta-analysis of the association of adiponectin gene polymorphisms with coronary heart disease in Chinese Han population.

OBJECTIVE: Variants of adiponectin gene have been reported to be associated with coronary heart disease (CHD), but the available data on this relationship are inconsistent. A meta-analysis was performed to quantitatively analyse the association of adiponectin gene polymorphisms with coronary artery disease using previous case-control studies in Chinese Han populations. METHODS: Several electronic databases were searched for relevant articles up to January 2011. After data collection and gene loci selection, a meta-analysis was performed to assess heterogeneity, combine results and evaluate variations. Publication bias was examined by the Egger's linear regression test. Hardy-Weinberg equilibrium (HWE) test and by omitting one study at a time was employed for the sensitivity analysis. RESULTS: Eleven studies covering 4303 subjects focusing on two polymorphisms [+45T→G (rs2241766) and +276G→T (rs1501299)] in the adiponectin gene and risk of CHD were included in the meta-analysis. Combined analyses of studies of the SNP+45 showed no significant overall association with CHD, yielding ORs of 1·03 (0·80, 1·34) and 1·32 (0·86, 2·03) under a dominant and recessive model, respectively, with strong evidence of heterogeneity. Similar results were also obtained in other genetic models. Concerning SNP+276, a significantly decreased CHD risk was observed under a dominant model, a codominant model and a allele contrast model, with an odds ratio of 0·67 (0·54, 0·83), 0·77 (0·62, 0·94) and 0·69 (0·55, 0·86), respectively. Sensitivity analysis confirmed the reliability and stability of this meta-analysis. CONCLUSIONS: The accumulated evidence suggested that the adiponectin gene polymorphism, SNP+45, is not associated with CHD, but the SNP+276T allele might be associated with decreased risk of CHD in the Chinese Han population. More well-designed large studies are required for the validation of this association.

Serum total adiponectin level and risk of cardiovascular disease in Han Chinese populations: a meta-analysis of 17 case-control studies.

OBJECTIVE: To systematically evaluate low serum adiponectin level as a risk factor for cardiovascular disease (CVD). A meta-analysis was performed to quantitatively analyse the association of serum total adiponectin level with CVD using previous case-control studies in Han Chinese populations. METHODS: Several electronic databases were searched for relevant articles up to July 2011. A total of nine (n = 933), eight (n = 939) articles were included in each meta-analysis regarding the association of serum adiponectin level with coronary heart disease (CHD) and ischaemic stroke, respectively. Publication bias was examined by the Egger's linear regression test. Sensitivity analysis was performed by omitting one study at a time, and the pooled standardized mean difference (SMD) was estimated using fixed-effects model and random-effects model, respectively. RESULTS: Serum total adiponectin concentrations were lower in patients with CHD and ischaemic stroke, with pooled SMD of -1·41 (95% CI -1·69, -1·12, P < 0·00001) and -1·69 (95% CI -2·04, -1·33, P < 0·00001), respectively. By performing a meta-regression analysis, homeostasis model assessment of insulin resistance, study size, adiponectin measurement assays, gender and mean body mass index of cases failed to account for heterogeneity for comparisons between lower adiponectin level and ischaemic stroke. However, study size had significant effect on the association of lower adiponectin level with CHD and accounted for 96·72% of the between-study variance. No publication bias was detected. No single study was found to affect the overall result of each analysis by sensitivity testing. CONCLUSIONS: The accumulated evidence suggested that low serum adiponectin level increased the risk of a first cardiovascular event in the Han Chinese population. Further study is recommended with larger sample size to explore the role of hypoadiponectinemia in the causation of CVD.

Salidroside decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice.

Salidroside is isolated from Rhodiola rosea and is one of the main active components in Rhodiola species. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD-) fed female LDL receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage) daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr(-/-) mice.

[A meta-analysis of early percutaneous coronary intervention within 24 hours of thrombolysis in acute ST-elevation myocardial infarction].

OBJECTIVE: To evaluate the efficacy and safety of early percutaneous coronary intervention (PCI) within 24 hours of thrombolysis in acute ST-elevation myocardial infarction. METHODS: The databases of Medline, EMBASE, Elsevier, Cochrane library, Wanfang and CNKI were searched for randomized controlled trials. Quality assessment and data extraction were performed by two independent reviewers. Statistical analyses were conducted with Stata 10.0 and RevMan 5.0 software. RESULTS: Eight studies (NORDI-STEMI, TRANSFER-AMI, WEST, CARESS-AMI, CAPITAL-AMI, GRACIA-I, SIAMI III & PRAGUE-I) involving a total of 3157 patients fulfilled the inclusion criteria. Meta-analysis results showed that, as compared with the control group, (1) the combined endpoint of 30 day mortality, re-infarction and ischemia was significantly lower in early PCI within 24 h of thrombolysis group [relative risk (RR) = 0.52, 95% confidence interval (CI) 0.42 - 0.65, P < 0.001]; (2) 30-day re-infarction decreased in early PCI within 24 h of thrombolysis group (RR = 0.57, 95%CI 0.40 - 0.81, P = 0.002); (3) 30-day ischemia had a significant reduction in early PCI within 24 h of thrombolysis group (RR = 0.27, 95%CI 0.14 - 0.52, P < 0.001); (4) 30-day major hemorrhage or mortality rates were not significantly different between two groups (RR = 1.07, 95%CI 0.78-1.46, P = 0.69; RR = 0.86, 95%CI 0.62 - 1.20, P = 0.38 respectively). CONCLUSION: When primary PCI is not feasible, our meta-analysis favors early PCI within 24 h of thrombolysis for acute ST-elevation myocardial infarction. Early PCI is associated with a lowered recurrence of major adverse cardiac events, ischemia and re-infarction. But there is no elevated risk of major hemorrhage and mortality.

Increased serum bile acid level is associated with high-risk coronary artery plaques in an asymptomatic population detected by coronary computed tomography angiography.

BACKGROUND: There are limited data on the association between serum total bile acid level and coronary plaque characteristics. This study investigated the relationship between serum total bile acid level and the severity of coronary stenosis and coronary plaque features in an asymptomatic population using coronary computed tomography angiography (CTA). METHODS: A total of 1,137 consecutive participants with no known coronary artery disease (CAD) undergoing CTA as part of a general routine health evaluation were recruited. Serum total bile acid level and clinical parameters were assayed. Coronary stenosis and high-risk plaques features (napkin-ring sign, low-attenuation plaque, spotty calcification, positive remodelling) were evaluated. Associations between serum total bile acid concentration and high-risk coronary plaques was tested through univariate and multivariate analyses. RESULTS: A total of 101 high-risk coronary plaques subjects and 93 controls were eligible for study inclusion. The severity of coronary artery stenosis and high-risk coronary plaques increased with serum total bile acid level quartiles (all P<0.001). The independent predictor of high-risk coronary plaques in multivariate analysis was serum total bile acid level (P<0.001). Receiver operating characteristic (ROC) confirmed that serum total bile acid concentration significantly differentiated high-risk coronary plaques [the area under the curve (AUC) =0.876; P<0.001, with a sensitivity of 87.13% and a specificity of 86.02%]. CONCLUSIONS: Higher serum total bile acid level was associated with the severity of coronary artery stenosis and high-risk coronary artery plaques detected by CTA in asymptomatic populations.

Luteolin alleviates NLRP3 inflammasome activation and directs macrophage polarization in lipopolysaccharide-stimulated RAW264.7 cells.

Pure plant extract luteolin has been demonstrated to possess numerous biological effects. However, the specific effect of luteolin on macrophage polarization and NOD-like receptor protein 3 (NLRP3) inflammasome activation has not been documented. In this study, Cultured RAW264.7 cells were treated with or without luteolin in the presence or absence of LPS. Subsequently, cell viability was tested by CCK-8 assay. Total reactive oxygen species (ROS) were measured by flow cytometry. NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1, inducible nitric oxide synthase (iNOS) and Arginase (Arg-1) protein expression was detected using western blotting. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the level of TNF-α, IL-18, and Interleukin-1ß (IL-1ß). Increased production of ROS and expression of NLRP3, ASC, caspase-1, IL-18 and IL-1ß proteins were observed in RAW264.7 cells incubated with LPS and were effectively inhibited by 2 µM luteolin. Furthermore, 2 µM luteolin pretreatment enhanced the expression of M2 macrophage markers (Arg-1 and IL-10), and decreased the expression of markers associated with M1 macrophage polarization (TNF-α, IL-6 and iNOS). These results indicated that low-dose luteolin inhibits NLRP3 inflammasomes activation and promotes macrophage polarization toward an M2 phenotype, which provides new evidence for the anti-inflammation activity of luteolin.

Qualitative and quantitative evaluation of dynamic changes in non-culprit coronary atherosclerotic lesion morphology: a longitudinal OCT study.

AIMS: There is limited in vivo evidence regarding the temporal evolution of non-culprit coronary plaque morphology. We aimed to evaluate changes in non-culprit plaque morphology over time by optical coherence tomography (OCT). METHODS AND RESULTS: Seventy-two (72) patients with 257 non-culprit segments with serial OCT studies were analysed. Non-culprit 5 mm-long coronary segments from the same imaged region were matched between baseline and follow-up. OCT plaque characterisation including automated attenuation analysis was performed, and changes over a median follow-up of 6.2 months were evaluated. On segment level, lumen area decreased from baseline to follow-up, whereas fibrous cap thickness increased. Similarly, plaque attenuation indices at follow-up were significantly decreased. Minimal cap thickness per patient did not change. In 68.5% of segments, plaque morphology did not change. Favourable change was observed in 18.4% of segments and unfavourable in 12.9%. There were no robust clinical predictors of change in plaque morphology. Attenuation analysis supported the qualitative characterisation, showing significantly different attenuation between different plaque types. CONCLUSIONS: In non-culprit coronary segments of patients with coronary artery disease under standard medical therapy, segment-level but not patient-level minimum fibrous cap thickness increases over time, with observations of both favourable and unfavourable changes in individual segments.

Conformability in everolimus-eluting bioresorbable scaffolds compared with metal platform coronary stents in long lesions.

The aim of this study was to determine if there are significant differences in curvature of the treated vessel after the deployment of a polymeric BRS or MPS in long lesions. The impact of long polymeric bioresorbable scaffolds (BRS) compared with metallic platform stents (MPS) on vessel curvature is unknown. This retrospective study compares 32 patients who received a single everolimus-eluting BRS with 32 patients treated with a single MPS of 28 mm. Quantitative coronary angiography (QCA) was used to evaluate curvature of the treatment and peri-treatment region before and after percutaneous coronary intervention (PCI). Baseline demographic and angiographic characteristics were similar between the BRS and MPS groups. Pretreatment lesion length was 22.19 versus 20.38 mm in the BRS and MPS groups respectively (p = 0.803). After treatment, there was a decrease in median diastolic curvature in the MPS group (from 0.257 to 0.199 cm-1, p = 0.001). A similar trend was observed in the BRS group but did not reach statistical significance (median diastolic curvature from 0.305 to 0.283 cm-1, p = 0.056). Median Percentage relative change in diastolic curvature was lower in the BRS group compared with the MPS group (BRS vs. MPS: 7.48 vs. 29.4%, p = 0.013). By univariate analysis, use of MPS was an independent predictor of change in diastolic curvature (p = 0.022). In the deployment of long coronary scaffolds/stents (28 mm in length), BRS provides better conformability compared with MPS.

Critical analysis of the correlation between optical coherence tomography versus intravascular ultrasound and fractional flow reserve in the management of intermediate coronary artery lesion.

The appropriate assessment of intermediate coronary artery stenosis continues to be a challenge for cardiologists. Several studies have shown that anatomic parameters obtained by intravascular ultrasound (IVUS) and optical coherence tomography (OCT) showed a correlation with fractional flow reserve (FFR) values in identifying hemodynamically severe coronary stenoses. However, the efficacy of IVUS/OCT versus FFR integration in intermediate coronary lesions is still debated. This review will allow for an independent analysis of research data and outlines the diagnostic efficiency of IVUS and OCT derived-anatomical parameters in identifying the hemodynamic significance of an angiographically intermediate stenosis as determined by FFR.

A meta-analysis of the risk of total cardiovascular events of isosmolar iodixanol compared with low-osmolar contrast media.

BACKGROUND: The iso-osmolar contrast agent iodixanol may be associated with a lower incidence of cardiac events than low-osmolar contrast media (LOCM), but previous trials have yielded mixed results. OBJECTIVE: To compare the risk of total cardiovascular events of the iso-osmolar contrast medium, iodixanol, to LOCM. METHODS: Medical literature databases were searched to identify comparisons between iodixanol and LOCM with cardiovascular events as a primary endpoint. A random-effects model was used to obtain pooled odds ratio (OR) for within-hospital and 30-day events. RESULTS: A total of 2 prospective cross-sectional studies and 11 randomized controlled trials (RCTs) (covering 6859 subjects) met our criteria. There was no significant difference in the incidence of within-hospital and 30-day cardiovascular events when iodixanol was compared with LOCM, with pooled OR of 0.72 (95%CI 0.49-1.06, p=0.09) and 1.19 (95%CI 0.70-2.02, p=0.53), respectively. Subgroup analysis showed no relative difference when iodixanol was compared with ioxaglate (OR=0.92, 95%CI 0.50-1.70, p=0.80) and iohexol (OR=0.75, 95%CI 0.48-1.17, p=0.21). However, a reduction in the within-hospital cardiovascular events was observed when iodixanol was compared with LOCM in the RCT subgroup (OR=0.65, 95%CI 0.44-0.96, p=0.03). Sensitivity analyses revealed that three studies had a strong impact on the association of within-hospital cardiovascular events between iodixanol and LOCM. Meta-regression analysis failed to account for heterogeneity. No publication bias was detected. CONCLUSIONS: This meta-analysis demonstrates that there is no conclusive evidence that iodixanol is superior to LOCM overall with regard to fewer cardiovascular events.

Acute impact of pacing at different cardiac sites on left ventricular rotation and twist in dogs.

OBJECTIVES: We evaluated the acute impact of different cardiac pacing sites on two-dimensional speckle-tracking echocardiography (STE) derived left ventricular (LV) rotation and twist in healthy dogs. METHODS: Twelve dogs were used in this study. The steerable pacing electrodes were positioned into right heart through the superior or inferior vena cava, into LV through aorta across the aortic valve. The steerable pacing electrodes were positioned individually in the right atrium (RA), right ventricular apex (RVA), RV outflow tract (RVOT), His bundle (HB), LV apex (LVA) and LV high septum (LVS), individual pacing mode was applied at 10 minutes interval for at least 5 minutes from each position under fluoroscopy and ultrasound guidance and at stabilized hemodynamic conditions. LV short-axis images at the apical and basal levels were obtained during sinus rhythm and pacing. Offline STE analysis was performed. Rotation, twist, time to peak rotation (TPR), time to peak twist (TPT), and apical-basal rotation delay (rotational synchronization index, RSI) values were compared at various conditions. LV pressure was monitored simultaneously. RESULTS: Anesthetic death occurred in 1 dog, and another dog was excluded because of bad imaging quality. Data from 10 dogs were analyzed. RVA, RVOT, HB, LVA, LVS, RARV (RA+RVA) pacing resulted in significantly reduced apical and basal rotation and twist, significantly prolonged apical TPR, TPT and RSI compared to pre-pacing and RA pacing (all P<0.05). The apical and basal rotation and twist values were significantly higher during HB pacing than during pacing at ventricular sites (all P<0.05, except basal rotation at RVA pacing). The apical TPR during HB pacing was significantly shorter than during RVOT and RVA pacing (both P<0.05). The LV end systolic pressure (LVESP) was significantly lower during ventricular pacing than during pre-pacing and RA pacing. CONCLUSIONS: Our results show that RA and HB pacing results in less acute reduction on LV twist, rotation and LVESP compared to ventricular pacing.

Association of TCF7L2 gene polymorphisms with type 2 diabetes mellitus in Han Chinese population: a meta-analysis.

Variants of transcription factor 7-like 2 (TCF7L2) gene have been reported to be associated with type 2 diabetes mellitus (T2DM), but the available data on this relationship are inconsistent in Han Chinese populations. A meta-analysis was performed to quantitatively analyze the association of TCF7L2 gene polymorphisms with T2DM using previous case-control studies in Chinese Han populations. Several electronic databases were searched for relevant articles up to May 2012. After data collection and gene loci selection, a meta-analysis was performed to assess heterogeneity, combine results and evaluate variations. Publication bias was examined by the Egger's linear regression test. Hardy-Weinberg equilibrium (HWE) test and by omitting one study at a time were employed for the sensitivity analysis. Eighteen studies from sixteen eligible papers were included in the meta-analysis. Ten eligible studies were analyzed for rs7903146, and eight were analyzed for rs290487. We found that the rs7903146 T allele was associated with an increased risk for T2DM under a dominant model, a co-dominant model and an allele contrast model, with an OR of 1.54 (1.32, 1.79), an OR of 1.53 (1.31, 1.79) and an OR of 1.52 (1.31, 1.76), respectively. The rs290487 C allele showed no significant overall association with T2DM, yielding ORs of 1.08 (0.88, 1.32) under a dominant model, with strong evidence of heterogeneity. Similar results were also obtained in other genetic models. Sensitivity analysis confirmed the reliability and stability of this meta-analysis. The accumulated evidence suggested that the rs7903146 T allele was associated with an increased risk for T2DM, but the rs290487 C allele is not associated with T2DM in the Chinese Han population. More well-designed large studies are required for the validation of this association.

Renoprotective effect of alprostadil in combination with statins in patients with mild to moderate renal failure undergoing coronary angiography.

BACKGROUND: The role of alprostadil and statins in contrast-induced acute kidney injury (CI-AKI) is controversial. The purpose of this study was to explore the efficacy of combined therapy with alprostadil and statins in protecting renal function and preventing contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. METHODS: A total of 156 consecutive patients with mild to moderate renal failure who underwent coronary angiography were enrolled in our study, and randomly categorized into two groups. In the statins group, 80 patients were treated with statins before and after coronary angiography. In the alprostadil plus statins group, 76 patients were treated with statins and alprostadil before and after coronary angiography. Serum creatinine (SCr), serum cystatin (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) were detected after administration of contrast media, and adverse events were evaluated within six months. RESULTS: In both groups, the SCr, CysC and NGAL significantly increased after coronary angiography and peaked at 48, 24 and 6 hours, respectively. SCr, CysC and NGAL were significantly lower in the alprostadil plus statins group than in the statins group (P < 0.05). The incidence of CIN in the alprostadil plus statins group was slightly lower than in the statins group. The incidence of adverse events within six months in the alprostadil plus statins group was significantly lower than in the statins group (P = 0.034). CONCLUSIONS: Intravenous alprostadil in combination with oral statins is superior to statins alone for protecting renal function in patients with mild to moderate renal dysfunction who undergo coronary angiography, and can reduce the incidence of adverse events seen within six months.

Tesaglitazar ameliorates non-alcoholic fatty liver disease and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient mice.

Previous research has demonstrated that the dual PPARα/γ agonist tesaglitazar reduces atherosclerosis in a mouse model of hyperlipidemia by reducing both lipid content and inflammation in the aorta. However, much of the underlying mechanism of tesaglitazar in non-alcoholic fatty liver disease (NAFLD) remains less clear. The aim of the present study was to determine whether tesaglitazar attenuates NAFLD and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice (3 weeks old) were induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection to develop an animal model of type 2 diabetes (T2DM). The mice were randomly divided into two groups: diabetic group (untreated diabetic mice, n=15) and tesaglitazar therapeutic group (n=15, 20 µg/kg/day oral treatment for 6 weeks). Fifteen LDLr(-/-) mice were fed with an HFD as the control group. Tesaglitazar decreased serum glucose and lipid levels compared with the diabetic mice. Tesaglitazar significantly reduced atherosclerotic lesions, lipid accumulation in the liver, macrophage infiltration, and decreased total hepatic cholesterol and triglyceride content compared to the diabetic mice. In addition, tesaglitazar reduced inflammatory markers at both the serum and mRNA levels. Our data suggest that tesaglitazar may be effective in preventing NAFLD and atherosclerosis in a pre-existing diabetic condition by regulating glucose and lipid metabolism, and the inflammatory response.

Initial clinical experience with implantation of left ventricular lead guided by Overlay Ref for the treatment of congestive heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves clinical outcome in selected patients with advanced congestive heart failure. The Overlay Ref technique may facilitate the procedure for implanting left ventricular (LV) pacing leads to deliver CRT. AIM: To assess the feasibility of deploying a LV pacing lead into a coronary sinus side branch guided by Overlay Ref. METHODS: Data from 88 consecutive patients who met the CRT implantation criteria in our hospital between 28 November 2007 and 30 December 2009 were randomly assigned to two groups. Forty-four patients underwent CRT device implantation using Overlay Ref to guide target vein selection and advance a specifically designed pacing lead into the target vein (Overlay Ref group); 44 patients were conventionally implanted (control group). RESULTS: LV lead implantation was successful in all patients. Mean CRT total procedure times (skin-to-skin) were: Overlay Ref group, 80.7 ± 18.0 min; control group, 98.5 ± 32.2 min; p = 0.029. Mean placement of LV pacing lead into target vein times were: Overlay Ref group, 16.2 ± 7.7 min; control group, 36.4 ± 23.4 min; p=0.004. Mean total fluoroscopy times were: Overlay Ref group, 13.6 ± 4.3 min; control group, 23.8 ± 15.7 min; p=0.007. Mean LV lead fluoroscopy times were: Overlay Ref group, 5.7 ± 2.9 min; control group, 14.4 ± 4.6 min; p=0.003. No major complications occurred. CONCLUSIONS: Overlay Ref facilitates location of and entry into the coronary sinus, and shortens the duration of LV pacing lead implantation into the target vein.